Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the roles of granisetron and dexamethasone for emesis control on days 2 through 7 after the administration of cisplatin in doses of 50 mg/m2 or greater to patients who had not previously received chemotherapy. PATIENTS AND METHODS: Four hundred thirty-five eligible and assessable patients were randomized to one of two arms in a double-blind fashion: arm A; granisetron 3 mg intravenous (i.v.) plus dexamethasone 10 mg i.v. prechemotherapy followed by granisetron 1 mg orally at 6 and 12 hours, then granisetron 1 mg orally and dexamethasone 8 mg orally twice daily on days 2 through 7 (219 patients); arm B; as in arm A but with placebo substituted for granisetron on days 2 through 7 (216 patients). All patients completed diaries in which episodes of emesis and severity of nausea were recorded. RESULTS: The addition of granisetron on days 2 through 7 had no discernable impact on nausea and vomiting during this period. CONCLUSION: The administration of a 5-hydroxytryptamine3, receptor (5-HT3) antagonist, in this case granisetron, after 24 hours conferred no benefit. This negative result needs to be assessed in light of conflicting literature, but at present it does not appear that the routine use of these drugs in this setting is justified.

A phase II trial of intravenous etoposide (VP-16-213) in epithelial ovarian cancer resistant to cisplatin or carboplatin: clinical and serological evidence of activity.

Etoposide (VP16) was administered intravenously at a dose of 150 mg/m2 daily for 2 days every 2 weeks to 24 patients with progressing epithelial ovarian carcinoma which was resistant to platinum analogues. Using standard response criteria there were five clinical partial responses (21%, 95% confidence limits 5-37%) and three disease stabilizations. However, the aim of our study was to determine if etoposide was non-cross-resistant with platinum analogues and therefore we also developed additional response criteria based on serial CA 125 levels. This was to enable us to differentiate within the heterogeneous group of responses that form the stable disease category. Nine of 23 patients (39%, 95% confidence limits 19-59%) demonstrated a fall (all rising prior to etoposide) and of these, three had a serologic partial remission (65% or greater fall). The serologic and clinical responses were strongly correlated. Falling CA 125 levels occurred in the eight patients with either clinical partial responses or disease stabilizations.

Platinum plus cyclophosphamide plus radiotherapy is superior to platinum alone in 'high-risk' epithelial ovarian cancer (residual negative and either stage I or II, grade 3, or stage III, any grade).

Patients with epithelial ovarian cancer (EOC) referred to our institution are stratified into risk groups based on their stage, grade and presence of residual cancer, with a specific treatment policy for each group. One-hundred and thirty-one patients with no visible residual tumor following primary surgery and either stage I, grade 3; stage II, grade 3; or stage III, any grade EOC were treated between November 1983 and the end of December 1991. Regimen A (cisplatin 75 mgm-2 and cyclophosphamide 600 mgm-2 intravenously every 4 weeks for 6 cycles with abdominopelvic irradiation between cycles 3 and 4) was used until April 1989 and was then replaced with Regimen B (cisplatin 75 mgm-2 intravenously every 3 weeks for 6 cycles). The 5-year actuarial overall and failure-free survivals were 78% and 64% respectively. Multivariate analysis identified increasing stage and treatment with Regimen B as independent adverse prognostic factors for failure-free survival. The importance of treatment regimen reached statistical significance for the stage I patients (P = 0.04) but not stage II (P = 0.11) or stage III (P = 0.79). It is possible to undertreat EOC as shown by the inferior results achieved with Regimen B (single agent cisplatin) compared to Regimen A (cisplatin-cyclophosphamide, irradiation). This effect of treatment regimen was particularly important for the lower-stage patients. Our postulate is that treatment resistant clones are less regularly present in lower-stage patients, and that a certain minimum amount of treatment is required to eliminate all the sensitive cancer.

'Moderate-risk' ovarian cancer (stage I, grade 2; stage II, grade 1 or 2) treated with cisplatin chemotherapy (single agent or combination) and pelvi-abdominal irradiation.

We placed patients with invasive epithelial ovarian cancer into four distinct prognostic groups: 'low', 'moderate', 'high' and 'extreme' risk. The 'moderate-risk' group contained all residual negative, stage I and II patients with two exceptions: stage Ia or b, grade 1 cancers and grade 3 cancers. They were treated with primary surgery, usually including bilateral salpingo-oophorectomy, hysterectomy and omentectomy. Chemotherapy was then given (cisplatin at 100 mg m-2 every 2 weeks for three cycles) followed by pelvi-abdominal irradiation (2250 cGy in 10 fractions to the pelvis and 2250 cGy in 22 fractions to the whole abdomen including pelvis). An early cohort with ascites or positive washings instead received six cycles of cisplatin and cyclophosphamide at 75 mg m-2 and 600 mg m-2 every 4 weeks with the same pelvi-abdominal irradiation sandwiched between cycles 3 and 4. One-hundred and nine patients were treated between November 1983 and December 1989. Median follow-up was 4.7 years (range 0.7-9 years). The 5-year actuarial overall and failure-free survivals were 81% and 76%, respectively. Chronic toxicity, although usually minor, included 15% with peripheral neuropathy or ototoxicity and 23% with chronic abdominal complaints. Our combined-modality results are similar to those obtained by other centers utilizing either pelvi-abdominal irradiation alone or cisplatin-based chemotherapy alone.

A phase II trial of mitomycin in patients with epithelial ovarian carcinoma resistant to cisplatin or carboplatin.

Intravenous bolus mitomycin was given at a dose of 10-12 mg/m2 to patients with epithelial ovarian cancer resistant to cisplatin or carboplatin. There were three (12%) partial responses and no complete responses in the 25 patients so treated.

Complete hydatidiform mole coexistent with a twin live fetus: clinical course of four cases with complete cytogenetic analysis.

Twin gestations can occur in which one twin is a normal gestation (46 chromosomes: 23 maternal and 23 paternal origin) and in which the other twin is a complete hydatidiform mole (46 chromosomes all of paternal origin). Case reports of four such combined pregnancies that presented to a single institution are provided. All cases had documentation of clinical information, cytogenetic analysis, and fetal and placental pathology. Three of the four pregnancies were terminated for medical indications despite information documenting the presence of a normal fetus. All three of these patients required subsequent chemotherapy. The fourth case was followed conservatively and resulted in the birth of a normal infant at 38 weeks gestation. We speculate that the factors that led to the need for termination of the pregnancy (aggressive growth of trophoblast) may predict the need for further therapy. A true assessment of the antenatal and malignant sequelae risks associated with these rare gestations awaits the collection of a larger series of patients.

Theophylline for the treatment of atrioventricular block after myocardial infarction.

OBJECTIVE: To show that second- or third-degree atrioventricular block occurring as an early complication of acute inferior myocardial infarction is mediated by adenosine. SETTING: Cardiac care unit. DESIGN: Uncontrolled, observational, hypothesis-driven study. PATIENTS: Patients who developed clinically significant atrioventricular nodal blockade within 4 hours of admission for acute inferior myocardial infarction. INTERVENTION: Theophylline, 100 mg/min intravenously to a maximum of 250 mg. MEASUREMENTS: Continuous multilead electrocardiographic monitoring before and after administration of theophylline. RESULTS: During a 6-month period, eight men who had had acute inferior myocardial infarction developed clinically significant atrioventricular block. Three had third-degree block, and five had high-grade second-degree block. In all patients, 1:1 atrioventricular nodal conduction was restored and normal sinus rhythm reappeared within 3 minutes of the administration of theophylline. All patients remained free of arrhythmia for at least 24 hours. CONCLUSIONS: Adenosine produced by the ischemic myocardium may induce atrioventricular nodal block. In our patients, atrioventricular nodal block was resistant to conventional therapy such as atropine, but it responded to the adenosine antagonist theophylline.

"MECCA": a developmental, dose-intensive, non-cross-resistant platinum-based chemotherapy for advanced ovarian cancer.

Twenty-nine women, ages 30-58 years, with advanced ovarian carcinoma were treated with a developmental combination chemotherapy regimen consisting of mitomycin C, etoposide, cisplatin, and carboplatin (MECCA). This protocol utilized the concepts of dose intensity, front-end loading, non-cross-resistance, and synergy. The median overall survival was 37 months with a 27% 5-year survival; the median failure-free survival was 15 months with a 14% 5-year failure-free rate. The predominant toxicity was hematologic and there was one toxic death (cardiac failure). The overall survival results are superior to our previous experience.

Rab17 and rab18, small GTPases with specificity for polarized epithelial cells: genetic mapping in the mouse.

The Rab subfamily of small GTPases plays an important role in the regulation of membrane traffic in eukaryotic cells. While most Rab proteins are equally expressed in polarized and nonpolarized cells, Rab17 and Rab18 show epithelial cell specificity. Here we report the genetic mapping of Rab17 and Rab18 on mouse chromosomes 1 and 18, respectively. We also discuss some implications of Rab17 and Rab18 mapping, including their candidacy for the mouse mutations ln (leaden), Tw (twirler), and ax (ataxia).

Effect of a diabetic state on myometrial ultrastructure and isolated uterine contractions in the rat.

Alterations in rat myometrial ultrastructure and in vivo uterine contractile responses to oxytocin were examined in estradiol-treated (40 micrograms/kg) euglycemic and streptozotocin-induced (85 mg/kg) diabetic rats. Myometrial morphology was examined 18, 24, and 36 hr after estradiol administration. At the time points examined, nuclei of myometrial cells from euglycemic and diabetic rats were pleomorphic and contained large areas of heterochromatin dispersed throughout the nuclei. Mitochondria were round to oval in shape and contained a dense matrix with cristae that extended across the mitochondria. Myofilaments were found in both euglycemic and diabetic cells but the relative number of myofilaments in diabetic cells appeared to be less than the number found in myometrial cells removed from euglycemic animals. The number of free cytoplasmic ribosomes in diabetic cells also appeared to be less than those found in euglycemic cells. In order to determine if apparent differences in the number of myofilament found in diabetic myometrial cells could be correlated with changes in uterine contractile responses to hormones, oxytocin dose-response curves (10(-8) to 10(-5) M) were examined in isolated uteri removed from saline-injected and estradiol-injected (24-hr pretreatments) euglycemic and diabetic rats. The maximal contractile responses (milligrams tension developed per milligrams tissue) in saline-injected euglycemic and diabetic rats were 49 +/- 5 and 36 +/- 4, respectively, while maximal contractile responses in estradiol-injected euglycemic and diabetic rats were 68 +/- 7 and 45 +/- 5, respectively. Maximal contractile responses induced by oxytocin in estradiol-treated diabetic uteri were significantly smaller than the contractile responses measured in euglycemic estradiol-treated uteri. This study demonstrates that estradiol-induced changes in both myometrial cell morphology and in vitro uterine contractile responses to oxytocin are altered in diabetic rats.

Small cell carcinoma of the cervix treated with concurrent radiotherapy, cisplatin, and etoposide.

A multimodality regimen of four cycles of cisplatin and etoposide with concurrent locoregional radiotherapy (XRT) has been, since May 1988, the standard therapy for women with small cell carcinoma of the cervix (SCCC). Prophylactic cranial irradiation was to be used in all but primary progressors. All 11 patients (median age 47; 4 with pure SCCC and 7 with mixed histology) seen by us were treated with this regimen. Only 1 patient progressed while on treatment. The 3-year overall and failure-free survivals were 28%. Four patients remain alive in first remission; the remaining 7 died (2 from toxicity, 5 from cancer). Although not statistically significant due to the small numbers, it appeared that the chance of long-term survival depended both on the amount of the cancer as indicated by the FIGO stage and size of the primary and also the performance status. The toxicity was significant with 70% experiencing severe neutropenia and 40% being admitted for control of emesis. This regimen is only appropriate for those women in whom all of the apparent tumor can be encompassed within a radiation field and who, in addition, have a performance status of 0 or 1. For the remainder it does not offer any chance of long-term survival and its toxicity renders it antipalliative.

Dexamethasone improves the efficacy of granisetron in the first 24 h following high-dose cisplatin chemotherapy.

The object of the study was to determine whether dexamethasone improved the efficacy of the serotonin receptor (5-HT3) antagonist granisetron in controlling acute (within 24 h) emesis in cancer patients receiving high-dose cisplatin chemotherapy and to ascertain whether continuation of granisetron after 24 h reduces the occurrence of delayed emesis. This randomised, double-blind, multicentre, three-arm study was conducted at 21 medical centres. A group of 292 nausea- and emesis-free patients with cancer, who had never had chemotherapy and were scheduled to receive at least 50 mg/m2 cisplatin, were given 3 mg granisetron i.v. in a 15-min infusion with or without 10 mg dexamethasone i.v. completed 5 min prior to high-dose cisplatin and 1 mg granisetron p.o. at +6 h and +12 h. Primary study end-points were control of emesis and nausea. Patients completed a self-report diary every 6 h for the first 24 h. At the end of the 24-h period, the patients who received dexamethasone had a significantly higher complete protection rate from emesis (64% compared to 39%) than those who received no steroid. Similarly, the dexamethasone-treated group had a significantly higher complete plus partial (0-2 emetic episodes) protection rate (84% compared to 64%). This study shows that dexamethasone markedly enhances the antiemetic efficacy of granisetron for acute-onset emesis in high-dose cisplatin chemotherapy.

Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis.

Few molecular events important to platelet biogenesis have been identified. Mice homozygous for the spontaneous, recessive mutation gunmetal (gm) have prolonged bleeding, thrombocytopenia, and reduced platelet alpha- and delta-granule contents. Here we show by positional cloning that gm results from a G-->A substitution mutation in a splice acceptor site within the alpha-subunit of Rab geranylgeranyl transferase (Rabggta), an enzyme that attaches geranylgeranyl groups to Rab proteins. Most Rabggta mRNAs from gm tissues skipped exon 1 and lacked a start codon. Rabggta protein and Rab geranylgeranyl transferase (GGTase) activity were reduced 4-fold in gm platelets. Geranylgeranylation and membrane association of Rab27, a Rab GGTase substrate, were significantly decreased in gm platelets. These findings indicate that geranylgeranylation of Rab GTPases is critical for hemostasis. Rab GGTase inhibition may represent a new treatment for thrombocytosis and clotting disorders.